This application is in response to PA-10-255 Behavioral Regulation Mechanisms of Alcohol Dependence and Related Phenotypes, which seeks to promote research on associations between regulation mechanisms and alcohol dependence, genetic and environmental factors conferring risk for alcohol dependence, and factors differentiating alcohol dependence from related externalizing behaviors. The proposed study of Operation Iraqi Freedom / Operation Enduring Freedom veterans utilizes a longitudinal burst design to model the dynamic course of PTSD symptoms, alcohol dependence, and associated conduct problems. We test hypotheses regarding underlying regulatory deficits, dissociation between dependence and other externalizing behaviors, and gene x environment interactions. PTSD is related to alcohol dependence as well as associated externalizing problems resulting in difficulties in social and occupational functioning (Frueh, et al., 2001; Hog et al., 2007; Mills et al., 2007; Seal et al., 2011). Research indicates that deficits in affect an behavioral regulation are two distinct pathways linking PTSD and alcohol-related problems (Miller et al., 2006). We propose that these two pathways are associated with different types of problems. Recent theory and research on negative reinforcement models of substance dependence have highlighted the role of affect lability, rather than mean levels of negative affect, in the development of dependence (Baker et al., 2004; Simons et al., 2009, 2010b; Weinstein et al., 2008). PTSD is associated with marked lability, and we posit that it is this variability in mood that confers risk for the development of alcohol dependence in this population. In contrast, we propose that conduct problems associated with PTSD and alcohol use are a function of behavioral disinhibition. Disinhibition mediates associations between PTSD and alcohol problems (Miller et al., 2006) and disinhibition is primarily associated with alcohol-related conduct problems rather than dependence symptoms (Simons et al., 2009; 2010b). Although trauma exposure is associated with the development of PTSD and alcohol problems, there is significant variability in these associations across persons. We hypothesize genotype at the serotonin transporter linked polymorphic region (5-HTTLPR) interacts with trauma exposure to predict PTSD symptoms and alcohol dependence, as well as the intermediary variables, affect lability and behavioral disinhibition. The study will test the role of regulation mechanisms in growth of symptoms over time, acute changes in the outcomes via person x situation effects, and test reciprocal effects of alcohol consumption on lability and PTSD symptoms. By integrating assessment of genetic and environmental risk, basic behavioral regulation deficits, and alcohol dependence and related conditions the study can improve our understanding of etiology, risk and resilience mechanisms, and potential mechanisms of therapeutic change. PUBLIC HEALTH RELEVANCE: This research will increase understanding of the development of alcohol-related problems, an important public health concern. It tests a cohesive model linking genetic factors and environmental stress to endophenotypes, affect lability and behavioral disinhibition associated with alcohol dependence and related conduct problems. We test this model using highly innovative in situ assessment techniques including experience sampling with PDAs and transdermal BAC monitoring. Prevention and intervention efforts can be most cost efficient and effective when guided by a solid understanding of the biological and psychological mechanisms underlying alcohol use disorder.